Cancer is a multigenic disease that involves the interplay of many gene products and many cell types. While much concentration has been placed on the identification of single genes that have a large effect on the process of tumor development, it is clear that no one single genetic change is sufficient for a normal cell to become malignant. While multiple genetic changes are present in tumor cells, one aspect of tumor development is the role of natural variation in the function of genes that are not mutated in cancer development. Determining the function of these "modifier" or "susceptibility" genes is vital to understanding the process of tumor development. Mice are excellent models with which to perform this type of study. Mice carrying the ApcMin allele are predisposed to develop mammary hyperplasias and tumors. Genetic background affects the type of lesion, the number of lesions, and tumor latency in the mammary glands of these mice. B6 ApcMin/+ mice rapidly develop squamous cell carcinomas of the mammary gland after exposure to a carcinogen. FVBxB6 ApcMin/+ mice develop mainly alveolar hyperplasias and carcinomas only rarely after the same treatment. To identify the genes responsible for this phenotypic difference, a backcross analysis was performed and several modifier loci have been identified. The goals of this project are to 1) generate congenic FVB ApcMin/+ mice in order to characterize the effect of the genetic background more completely; 2) generate and characterize congenic lines of mice that carry either the FVB or 129 allele of one of the modifiers, Mmom2; and 3) to map Mmom2 to a interval small enough to allow genetic identification of the loci;4) to further characterize the molecular phenotype conferred by Mmom2; and 5) to use changes in gene expression to identify molecular pathways affected by Mmom2. The ultimate goals of these studies are to identify the gene encoding Mmom2 and understand the effect on tumor development. Understanding how this gene product can alter the fate of initiated cells will inform the development of targeted treatments and treatment strategies for women who have been diagnosed with preneoplastic lesions in the breast. PUBLIC HEALTH RELEVANCE: Breast cancer shows a strong familial tendency, but most cases cannot be ascribed to the effect of major genes. Thus, most cases of breast cancer will be due to the sum of the effects of genes with smaller, though significant effects. The goal of this project is to identify and characterize the function of one such locus using a mouse model. [unreadable] [unreadable] [unreadable] [unreadable]